The importance of fluorine in altering the physicochemical properties of organic molecules and its exploitation in medicinal chemistry has been highlighted in recent reviews (Bohm, Banner et al. 2004). Although similar in size to hydrogen, H→F substitutions can cause dramatic effects on several properties of organic molecules, including the lipophilicity, dipole moment, and pKa thereof. In addition, fluorine substitutions can dramatically alter the reactivity of the fluorinated site as well as that of neighboring functional groups.
In particular, in medicinal chemistry, there is a growing interest towards incorporating fluorine atoms in building blocks, lead compounds and drugs in that this may increase by many-fold the chances of turning these molecules into marketable drugs. Several studies have shown that potent drugs can be obtained through fluorination of much less active precursors. Some representative examples include anticholesterolemic Ezetimib (Clader 2004), anticancer CF3-taxanes (Ojima 2004), fluoro-steroids, and antibacterial fluoroquinolones.
The improved pharmacological properties of fluoro-containing drugs are often due to their improved pharmacokinetic properties (biodistribution, clearance) and enhanced metabolic stability (Park, Kitteringham et al. 2001). Primary metabolism of drugs in humans generally occurs through P450-dependent systems, and the introduction of fluorine atoms at or near the sites of metabolic attack has often proven successful in increasing the half-life of a compound (Bohm, Banner et al. 2004). A comprehensive review covering the influence of fluorination on drug metabolism (especially P450-dependent) is presented (Park, Kitteringham et al. 2001).
In other cases, the introduction of fluorine substituents leads to improvements in the pharmacological properties as a result of enhanced binding affinity of the molecule to biological receptors. Examples of the effect of fluorine on binding affinity are provided by recent results in the preparation of NK1 antagonists (Swain and Rupniak 1999), 5HT1D agonists (van Niel, Collins et al. 1999), and PTB1B antagonists (Burke, Ye et al. 1996).
Over the past years, fluorination has been playing an increasingly important role in drug discovery, as exemplified by the development of fluorinated derivatives of the anticancer drugs paclitaxel and docetaxel (Ojima 2004).
However, only a handful of organofluorine compounds occur in nature and even those are found in very small amounts (Harper and O'Hagan 1994). Consequently, any fluorine-containing substance selected for research, pharmaceutical, or agrochemical application has to be man-made.
Despite a few reports on the application of molecular fluorine (F2) for direct fluorination of organic compounds (Chambers, Skinner et al. 1996; Chambers, Hutchinson et al. 2000), this method typically suffers from poor selectivity and requires handling of a highly toxic and gaseous reagent. Several chemical strategies have been developed over the past decades to afford selective fluorination of organic compounds under friendlier conditions. These have been recently reviewed by Togni (Togni, Mezzetti et al. 2001), Cahard (Ma and Cahard 2004), Sodeoka (Hamashima and Sodeoka 2006), and Gouverneur (Bobbio and Gouverneur 2006). These strategies involve catalytic as well as non-catalytic methods. The latter comprise substrate-controlled fluorination methods, which generally make use of a chiral auxiliary, and reagent-controlled fluorination methods, which generally make use of chiral electrophilic N—F or nucleophilic fluorinating reagents.
These fluorination methods, however, need several chemical steps to prepare the chiral substrates (Davis and Han 1992; Enders, Potthoff et al. 1997) or the chiral reagents (Davis, Zhou et al. 1998; Taylor, Kotoris et al. 1999; Nyffeler, Duron et al. 2005) and have an applicability restricted to reactive C—H bonds (Cahard, Audouard et al. 2000; Shibata, Suzuki et al. 2000; Kim and Park 2002; Beeson and MacMillan 2005; Marigo, Fielenbach et al. 2005) in specific classes of compounds such as aldehydes (Beeson and MacMillan 2005; Marigo, Fielenbach et al. 2005) or di-carbonyls (Hintermann and Togni 2000; Ma and Cahard 2004; Shibata, Ishimaru et al. 2004; Hamashima and Sodeoka 2006).
Despite much progress in the field of organofluorine chemistry, the number of available methods for direct or indirect asymmetric synthesis of organofluorine compounds remains limited and additional tools are desirable. In particular, a general method to afford mono- or poly-fluorination of organic compounds at reactive and unreactive sites of their molecular scaffold is desirable.